Functional Consequences of 17q21.31/WNT3-WNT9B Amplification in HPSCs with Respect to Neural Differentiation

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2015 Feb 3

PMID 25640183

Citations 20

Authors

Chun-Ting Lee

Raphael M Bendriem

Abigail A Kindberg

Lila T Worden

Melanie P Williams

Tomas Drgon

Barbara S Mallon

Brandon K Harvey

Christopher T Richie

Rebecca S Hamilton

Jia Chen

Stacie L Errico

Shang-Yi A Tsai

George R Uhl

William J Freed

Affiliations

Soon will be listed here.

Abstract

Human pluripotent stem cell (hPSC) lines exhibit repeated patterns of genetic variation, which can alter in vitro properties as well as suitability for clinical use. We examined associations between copy-number variations (CNVs) on chromosome 17 and hPSC mesodiencephalic dopaminergic (mDA) differentiation. Among 24 hPSC lines, two karyotypically normal lines, BG03 and CT3, and BG01V2, with trisomy 17, exhibited amplification of the WNT3/WNT9B region and rapid mDA differentiation. In hPSC lines with amplified WNT3/WNT9B, basic fibroblast growth factor (bFGF) signaling through mitogen-activated protein kinase (MAPK)/ERK amplifies canonical WNT signaling by phosphorylating LRP6, resulting in enhanced undifferentiated proliferation. When bFGF is absent, noncanonical WNT signaling becomes dominant due to upregulation of SIAH2, enhancing JNK signaling and promoting loss of pluripotency. When bFGF is present during mDA differentiation, stabilization of canonical WNT signaling causes upregulation of LMX1A and mDA induction. Therefore, CNVs in 17q21.31, a "hot spot" for genetic variation, have multiple and complex effects on hPSC cellular phenotype.

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